Medical and neurobehavioural phenotypes in carriers of X-linked ichthyosis-associated genetic deletions in the UK Biobank

Abstract

BackgroundX-linked ichthyosis (XLI) is an uncommon dermatological condition resulting from a deficiency of the enzyme steroid sulfatase (STS), often caused by X-linked deletions spanning STS. Some medical comorbidities have been identified in XLI cases, but small samples of relatively young patients has limited this. STS is highly expressed in subcortical brain structures, and males with XLI and female deletion carriers appear at increased risk of developmental/mood disorders and associated traits; the neurocognitive basis of these findings has not been examined.MethodsUsing the UK Biobank resource, comprising participants aged 40–69 years recruited from the general UK population, we compared multiple medical/neurobehavioural phenotypes in males (n=86) and females (n=312) carrying genetic deletions spanning STS (0.8–2.5 Mb) (cases) to male (n=190 577) and female (n=227 862) non-carrier controls.ResultsWe identified an elevated rate of atrial fibrillation/flutter in male deletion carriers (10.5% vs 2.7% in male controls, Benjamini-Hochberg corrected p=0.009), and increased rates of mental distress (p=0.003), irritability (p<0.001) and depressive-anxiety traits (p<0.05) in male deletion carriers relative to male controls completing the Mental Health Questionnaire. While academic attainment was unaffected, male and female deletion carriers exhibited impaired performance on the Fluid Intelligence Test (Cohen’s d≤0.05, corrected p<0.1). Neuroanatomical analysis in female deletion carriers indicated reduced right putamen and left nucleus accumbens volumes (Cohen’s d≤0.26, corrected p<0.1).ConclusionAdult males with XLI disease-causing deletions are apparently at increased risk of cardiac arrhythmias and self-reported mood problems; altered basal ganglia structure may underlie altered function and XLI-associated psychiatric/behavioural phenotypes. These results provide information for genetic counselling of deletion-carrying individuals and reinforce the need for multidisciplinary medical care.

Medical and neurobehavioural phenotypes in male and female carriers of Xp22.31 duplications in the UK Biobank

“…We identified ICD-10 unique descriptive codes that were the most common in duplication carriers (present in at least 1 in 40 (>2.5%) carriers), and that were also recorded in a significant proportion (>1.5%) of individuals in the overall male and female samples; these selection criteria, analogous to those used in our previous Xp22.31 deletion study ( 3 ), were designed to detect robust between-group effects. 13 ICD-10 codes met these criteria in the male sample ( Supplementary Material, Table 2 ).…”

“…XLI predominantly affects males, and is associated with a number of conditions including cryptorchidism and benign corneal opacities; some female deletion carriers also have corneal opacities and can exhibit prolonged/delayed labour during childbirth as a consequence of STS deficiency in the fetal portion of the placenta ( 2 ). We have recently shown that males with deletions spanning STS are at significantly increased risk of atrial fibrillation/flutter compared to male non-carriers ( 3 ). Occasional comorbidities with XLI can include focal epilepsy ( 4 ), pyloric hypertrophy, congenital defect of the abdominal wall, acute lymphoblastic leukaemia, bilateral periventricular nodular heterotopia and end-stage renal failure ( 2 ).…”

“…Occasional comorbidities with XLI can include focal epilepsy ( 4 ), pyloric hypertrophy, congenital defect of the abdominal wall, acute lymphoblastic leukaemia, bilateral periventricular nodular heterotopia and end-stage renal failure ( 2 ). Deletions around STS are also associated with substantially elevated rates of developmental disorders (notably autism and inattentive Attention Deficit Hyperactivity Disorder (ADHD)) ( 5–7 ), and with elevated rates of associated cognitive, motor and mood symptoms ( 3 , 8 , 9 ); these psychological features may stem from subcortical brain structure differences, notably a reduction in the size of some regions of the basal ganglia ( 3 ). Rare, larger genetic deletions around STS are associated with a number of more severe neurological conditions including Kallman, Rud, and Conradi syndromes ( 2 ).…”

A novel STS mutation and an Xp22.3 microdeletion from one Chinese family with X-linked ichthyosis

“…In addition, neurodevelopmental conditions, including ADHD, autism, and mental retardation, were also observed in patients with XLI [16,17]. Recently, a study showed adult males with XLI disease-causing deletions are apparently at increased risk of cardiac arrhythmias and self-reported mood problems [10], and altered basal ganglia structure was observed in these patients [10]. In this pedigree in the present study, the patient III:6, who had ichthyosis, mental retardation, delayed speech, and history of febrile convulsion, was found to harbor a Xp22.31 deletion of 1.98 Mb, and the patient has not yet showed heart rhythm problems at the age of 35 years old.…”

“…Patients with mutations involving solely the STS gene may present with attention de cit hyperactivity disorder (ADHD), while those with deletions including neighboring genes such as neuroligin 4 (NLGN4) may be associated with multiple neurodevelopmental disorders, including mental retardation, autism spectrum disorders (ASDs), ADHD, and seizures [4]. In addition, a recent study showed adult males with XLI disease-causing deletions are apparently at increased risk of cardiac arrhythmias and self-reported mood problems [10].…”